Background
The use of high‐definition transcranial direct current stimulation (HD‐tDCS) has shown analgesic effects in some chronic pain patients, but limited anti‐nociceptive effects in healthy ...asymptomatic subjects.
Methods
This double‐blinded sham‐controlled study assessed the effects of HD‐tDCS applied on three consecutive days on central pain mechanisms in healthy participants with (N = 40) and without (N = 40) prolonged experimental pain induced by intramuscular injection of nerve growth factor into the right hand on Day 1. Participants were randomly assigned to Sham‐tDCS (N = 20 with pain, N = 20 without) or Active‐tDCS (N = 20 with pain, N = 20 without) targeting simultaneously the primary motor cortex and dorsolateral prefrontal cortex for 20 min with 2 mA stimulation intensity. Central pain mechanisms were assessed by cuff algometry on the legs measuring pressure pain sensitivity, temporal summation of pain (TSP) and conditioned pain modulation (CPM), at baseline and after HD‐tDCS on Day 2 and Day 3. Based on subject's assessment of received HD‐tDCS (sham or active), they were effectively blinded.
Results
Compared with Sham‐tDCS, Active‐tDCS did not significantly reduce the average NGF‐induced pain intensity. Tonic pain‐induced temporal summation at Day 2 and Day 3 was significantly lower in the NGF‐pain group under Active‐tDCS compared to the pain group with Sham‐tDCS (p ≤ 0.05). No significant differences were found in the cuff pressure pain detection/tolerance thresholds or CPM effect across the 3 days of HD‐tDCS in any of the four groups.
Conclusion
HD‐tDCS reduced the facilitation of TSP caused by tonic pain suggesting that efficacy of HD‐tDCS might depend on the presence of sensitized central pain mechanisms.
Homeostatic plasticity complements synaptic plasticity by stabilising neural activity within a physiological range. In humans, homeostatic plasticity is investigated using two blocks of non‐invasive ...brain stimulation (NIBS) with an interval without stimulation between blocks. The aim of this systematic review and meta‐analysis was to investigate the effect of homeostatic plasticity induction protocols on motor evoked potentials (MEP) in healthy participants. Four databases were searched (Medline, Scopus, Embase and Cochrane library). Studies describing the application of two blocks of NIBS of the primary motor cortex with an interval of no stimulation between blocks reporting changes in corticospinal excitability by MEP amplitude were included. Thirty‐seven reports with 55 experiments (700 participants) were included. Study quality was considered poor overall, with heterogeneity in study size, sample and designs. Two blocks of excitatory stimulation at the primary motor cortex produced a homeostatic response (decreased MEP) between 0 and 30 min post‐protocols, when compared with a single stimulation block. Two blocks of inhibitory stimulation at the primary motor cortex using interval duration of 10 min or less produced a homeostatic response (increased MEP) between 0 and 30 min post‐protocols, when compared with a single stimulation block. There were no differences in MEPs when compared with baseline MEPs. In conclusion, homeostatic plasticity induction using two blocks of NIBS with an interval of 10 min or less without stimulation between blocks produces a homeostatic response up to 30 min post‐protocol. Improvements in participant selection, sample sizes and protocols of NIBS techniques are needed.
Background
A subset of osteoarthritis patients will experience chronic postoperative pain after total knee arthroplasty (TKA), but the source of pain is unclear. The aim of this exploratory study was ...to assess patients with and without postoperative pain after TKA using magnetic resonance imaging (MRI), quantitative sensory testing (QST), clinical assessment of pain and assessments of catastrophizing thoughts.
Methods
Forty‐six patients completed the 6‐month postoperative assessment. MRI findings were scored according to the MRI Osteoarthritis Knee Score recommendation for Hoffa synovitis, effusion size and bone marrow lesions. QST included assessment of pressure pain thresholds (PPTs), temporal summation of pain (TSP) and conditioned pain modulation (CPM). Pain catastrophizing was assessed using the Pain Catastrophizing Scale (PCS). Clinical pain assessment was conducted using a visual analogue scale (VAS, 0–10 cm), and groups of moderate‐to‐severe (VAS > 3) and none‐to‐mild postoperative pain (VAS ≤ 3) were identified.
Results
Patients with moderate‐to‐severe postoperative pain (N = 15) demonstrated higher grades of Hoffa synovitis (p < 0.001) and effusion size (p < 0.001), lower PPTs (p = 0.039), higher TSP (p = 0.001) and lower CPM (p = 0.014) when compared with patients with none‐to‐mild postoperative pain (N = 31). No significant difference was found in PCS scores between the two groups. Multiple linear regression models found synovitis (p = 0.036), effusion size (p = 0.003), TSP (p = 0.013) and PCS (p < 0.001) as independent parameters contributing to the postoperative pain intensity.
Conclusion
These exploratory findings could indicate that chronic postoperative pain after TKA is a combination of joint‐related synovitis and effusion, sensitization of central pain mechanisms and potentially pain catastrophizing thoughts, but larger studies are needed to confirm this.
Significance
The end‐stage treatment of knee osteoarthritis is total knee arthroplasty. Some patients experience chronic postoperative pain after total knee arthroplasty, but the mechanism for chronic postoperative pain is widely unknown. The current study indicates that higher levels postoperative of synovitis and effusion, higher temporal summation of pain and higher pain catastrophizing scores could be associated with higher chronic postoperative pain.
The aim of this Review is to give a short presentation of the manifestations, assessment methods, and mechanisms underlying localized and widespread musculoskeletal pain, deep somatic tissue ...hyperalgesia and chronification. Hyperalgesia can be explained by increased pain sensitivity of nociceptors located in deep tissue (peripheral sensitization) or by increased responses from dorsal horn neurons (central sensitization). The spreading of pain and sensitization is related to increased synaptic activity in central neurons and to changes in descending control from supraspinal centers. Manifestations related to the different aspects of sensitization can be assessed quantitatively using sensory tests, such as pressure algometry (quantitative palpation) and cuff-algometry. Repeated pressure stimulation can evaluate the degree of temporal summation, which is a proxy for the level of central sensitization, as is expanded referred muscle pain area. The transition of acute localized musculoskeletal pain into chronic widespread pain is related to the progression of peripheral and central sensitization. This sensitization for the chronification of pain should be assessed by adequate pain biomarkers. Furthermore, pain prevention should target early intervention strategies and new anti-hyperalgesic compounds should be developed.
Background
Antinociceptive effects of transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) have been extensively studied in the past years. However, M1 does not work in ...isolation, but it rather interacts within a network, the so‐called resting‐state motor network.
Objective
To explore the anti‐nociceptive effects of a new multifocal tDCS approach administered to regions linked to the resting state motor network (network‐tDCS) compared to sham tDCS.
Methods
Healthy individuals were included in this randomized, parallel and double‐blinded study comprising two consecutive interventions with 24‐hr interval of either active (n = 19) or sham (n = 19) network‐tDCS. Prolonged pain was induced by application of topical capsaicin on the dorsum of the hand during a 24‐hr period. Assessments of corticomotor excitability (transcranial magnetic stimulation), pain ratings (numerical rating scale, NRS), skin pain sensitivity on the arm (heat and mechanical), temporal summation of pain (TSP) and conditioned pain modulation (CPM) were performed at baseline (Day1‐baseline), after 25 min of capsaicin application and before the first tDCS session (Day1‐post‐cap), and after the second tDCS session (Day2).
Results
Comparing Day2 to Day1‐baseline measures, there was reduced corticomotor excitability (p < .05) and impaired CPM‐effect (p < .05) after sham but not after active network‐tDCS. Pain NRS ratings increased at Day2 compared to Day1‐post‐cap (p < .01) in both groups whereas no significant changes were found in pain sensitivity and TSP.
Conclusions
Present findings demonstrate that tDCS applied over regions linked to the resting state motor network reverts the inhibition of corticomotor excitability and CPM impairment both provoked by prolonged experimental pain for 24 hr.
Significance
These findings highlight that the stimulation of the resting state motor network with multifocal tDCS may represent a potential cortical target to treat chronic pain, particularly in patients exhibiting maladaptive corticomotor excitability and impaired conditioned pain modulation effects.
Cold pressor pain and exercise causes multisegmental increases in pressure pain thresholds. Exercise is dominated by local manifestations of hypoalgesia, whereas cold pressor pain results generally ...in remote hypoalgesia.
Pain inhibitory mechanisms are often assessed by paradigms of exercise-induced hypoalgesia (EIH) and conditioned pain modulation (CPM). In this study it was hypothesized that the spatial and temporal manifestations of EIH and CPM were comparable. The participants were 80 healthy subjects (40 females), between 18 and 65years of age in this randomized, repeated-measures cross-over trial that involved data collection on 2 different days. CPM was assessed by 2 different cold pressor tests (hand and foot). EIH was assessed by 2 intensities of aerobic bicycling exercises and 2 intensities of isometric muscle contraction exercises (arm and leg). Pressure pain thresholds (PPTs) were recorded before, during, after, and 15minutes after conditioning/exercise at sites local to and remote from the extremity used for cold pressor stimulation and exercise. PPTs increased at local as well as at remote sites during both cold pressor tests and after all of the exercise conditions except low-intensity bicycling. EIH after bicycling was higher in women than in men. CPM and the EIH responses after isometric exercises were comparable in men and women and were not affected by age. The EIH response was larger in the exercising body part compared with nonexercising body parts for all exercise conditions. High-intensity exercise produced greater EIH responses than did low-intensity exercise. The change in PPTs during cold pressor tests and the change in PPTs after exercises were not correlated. The CPM response was not dominated by local manifestations, and the effect was seen only during the stimulation, whereas exercise had larger local manifestations, and the effects were also found after exercise.
Background
Alterations in the default mode network (DMN) connectivity across pain stages suggest a possible DMN involvement in the transition to persistent pain.
Aim
This study examined whether ...pain‐free DMN connectivity at lower alpha oscillations (8‐10 Hz) accounts for a unique variation in experimental peak pain intensity beyond the contribution of factors known to influence pain intensity.
Methods
Pain‐free DMN connectivity was measured with electroencephalography prior to 1 h of capsaicin‐evoked pain using a topical capsaicin patch on the right forearm. Pain intensity was assessed on a (0–10) numerical rating scale and the association between peak pain intensity and baseline measurements was examined using hierarchical multiple regression in 52 healthy volunteers (26 women). The baseline measurements consisted of catastrophizing (helplessness, rumination, magnification), vigilance, depression, negative and positive affect, sex, age, sleep, fatigue, thermal and mechanical pain thresholds and DMN connectivity (medial prefrontal cortex mPFC‐posterior cingulate cortex PCC, mPFC‐right angular gyrus rAG, mPFC‐left Angular gyrus lAG, rAG‐mPFC and rAG‐PCC).
Results
Pain‐free DMN connectivity increased the explained variance in peak pain intensity beyond the contribution of other factors (ΔR2 = 0.10, p = 0.003), with the final model explaining 66% of the variation (R2 = 0.66, ANOVA: p < 0.001). In this model, negative affect (β = 0.51, p < 0.001), helplessness (β = 0.49, p = 0.007), pain‐free mPFC‐lAG connectivity (β = 0.36, p = 0.003) and depression (β = −0.39, p = 0.009) correlated significantly with peak pain intensity. Interestingly, negative affect and depression, albeit both being negative mood indices, showed opposing relationships with peak pain intensity.
Conclusions
This work suggests that pain‐free mPFC‐lAG connectivity (at lower alpha) may contribute to individual variations in pain‐related vulnerability.
Significance
These findings could potentially lead the way for investigations in which DMN connectivity is used in identifying individuals more likely to develop chronic pain.
Background
Diffuse noxious inhibitory controls (DNIC) as measured in rat and conditioned pain modulation (CPM), the supposed psychophysical paradigm of DNIC measured in humans, are unique ...manifestations of an endogenous descending modulatory pathway that is activated by the application of a noxious conditioning stimulus. The predictive value of the human CPM processing is crucial when deliberating the translational worth of the two phenomena.
Methods
For CPM or DNIC measurement, test and conditioning stimuli were delivered using a computer‐controlled cuff algometry system or manual inflation of neonate blood pressure cuffs, respectively. In humans (n = 20), cuff pain intensity (for pain detection and pain tolerance thresholds) was measured using an electronic visual analogue scale. In isoflurane‐anaesthetized naïve rats, nociception was measured by recording deep dorsal horn wide dynamic range (WDR) neuronal firing rates (n = 7) using in vivo electrophysiology.
Results
A painful cuff‐pressure conditioning stimulus on the leg increased pain detection and pain tolerance thresholds recorded by cuff stimulation on the contralateral leg in humans by 32% ± 3% and 24% ± 2% (mean ± SEM) of baseline responses, respectively (p < .001). This finding was back‐translated by revealing that a comparable cuff‐pressure conditioning stimulus (40 kPa) on the hind paw inhibited the responses of WDR neurons to noxious contralateral cuff test stimulation to 42% ± 9% of the baseline neuronal response (p = .003).
Conclusions
These data substantiate that the noxious cuff pressure paradigm activates the descending pain modulatory system in rodent (DNIC) and man (CPM), respectively. Future back and forward translational studies using cuff pressure algometry may reveal novel mechanisms in varied chronic pain states.
Significance
This study provides novel evidence that a comparable noxious cuff pressure paradigm activates a unique form of endogenous inhibitory control in healthy rat and man. This has important implications for the forward translation of bench and experimental pain research findings to the clinical domain. If translatable mechanisms underlying dysfunctional endogenous inhibitory descending pathway expression (previously evidenced in painful states in rat and man) were revealed using cuff pressure algometry, the identification of new analgesic targets could be expedited.
•Aerobic and resistance exercise typically lead to hypoalgesia in pain-free adults.•Exercise may lead to hypoalgesia or hyperalgesia in people with chronic pain.•Several different factors may ...influence the effect of exercise on pain.
Exercise is considered an important component of effective chronic pain management and it is well-established that long-term exercise training provides pain relief. In healthy, pain-free populations, a single bout of aerobic or resistance exercise typically leads to exercise-induced hypoalgesia (EIH), a generalized reduction in pain and pain sensitivity that occurs during exercise and for some time afterward. In contrast, EIH is more variable in chronic pain populations and is more frequently impaired; with pain and pain sensitivity decreasing, remaining unchanged or, in some cases, even increasing in response to exercise. Pain exacerbation with exercise may be a major barrier to adherence, precipitating a cycle of physical inactivity that can lead to long-term worsening of both pain and disability. To optimize the therapeutic benefits of exercise, it is important to understand how EIH works, why it may be impaired in some people with chronic pain, and how this should be addressed in clinical practice. In this article, we provide an overview of EIH across different chronic pain conditions. We discuss possible biological mechanisms of EIH and the potential influence of sex and psychosocial factors, both in pain-free adults and, where possible, in individuals with chronic pain. The clinical implications of impaired EIH are discussed and recommendations are made for future research, including further exploration of individual differences in EIH, the relationship between exercise dose and EIH, the efficacy of combined treatments and the use of alternative measures to quantify EIH.
This article provides a contemporary review of the acute effects of exercise on pain and pain sensitivity, including in people with chronic pain conditions. Existing findings are critically reviewed, clinical implications are discussed, and recommendations are offered for future research.
Background
Sensitized pain mechanisms are often reported in musculoskeletal pain conditions, but population‐based paediatric studies are lacking. We assessed whether adolescents with musculoskeletal ...pain history had evidence of increased responsiveness to experimental pressure stimuli.
Methods
Data were from 1496 adolescents of the Generation XXI birth cohort. Pain history was collected using the Luebeck Pain Questionnaire (self‐reported at 13, parent‐reported at 7 and 10 years). Two case definitions for musculoskeletal pain were considered: (1) cross‐sectional—musculoskeletal pain lasting more than 3 months at age 13 and (2) longitudinal—musculoskeletal pain at age 13 with musculoskeletal pain reports at ages 7 and/or 10. Lower limb cuff pressure algometry was used to assess pain detection and tolerance thresholds, conditioned pain modulation effects (CPM, changes in thresholds in the presence on painful conditioning) and temporal summation of pain effects (TSP, changes in pain intensity to 10 phasic painful cuff stimulations).
Results
Adolescents with musculoskeletal pain at age 13 plus a history of pain in previous evaluations (longitudinal definition) had lower pain tolerance thresholds compared to the remaining sample (40.2 v. 49.0 kPa, p = 0.02), but showed no differences in pain detection threshold, CPM effect and TSP effect. Pain sensitivity, CPM effects and TSP effects were not significantly different when the current pain only case definition (cross‐sectional) was used.
Conclusions
Adolescents with current musculoskeletal pain who had a history of pain since childhood had lower tolerance to cuff stimulation. This may suggest long‐standing musculoskeletal pain since childhood may contribute to sensitisation, rather than the presence of current pain only.
Significance
Repeated musculoskeletal pain up to age 13 years may contribute to higher pain sensitivity (particularly lowered pressure pain tolerance) in the general adolescent population. This does not seem to be the case when reported pain experiences are recent or when the outcomes are temporal pain summation or CPM. In this community‐based paediatric sample, the vast majority showed no sign of altered pain processing, but a small fraction may reveal some pain sensitization at 13 years of age.
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